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United States Patent |
6,017,917
|
Kuno
,   et al.
|
January 25, 2000
|
Guanidine derivatives
Abstract
Guanidine derivatives of the formula:
##STR1##
wherein R.sup.1 is [di(lower)alkylamino](lower)alkyl,
morpholinyl(lower)alkyl, lower alkylpiperazinyl or [lower
alkylpyrrolidinyl](lower)alkyl,
R.sup.2 is halogen, lower alkyl or lower alkoxy, and
R.sup.3 is halogen, lower alkyl, lower alkoxy or mono(or di or
tri)halo(lower)alkyl,
and pharmaceutically acceptable salts thereof which are useful as a
medicament.
Inventors:
|
Kuno; Atsushi (Osaka, JP);
Inoue; Yoshikazu (Osaka, JP);
Yamasaki; Kumi (Nishinomiya, JP)
|
Assignee:
|
Fujisawa Pharamceutical Co., Ltd. (Osaka, JP)
|
Appl. No.:
|
091825 |
Filed:
|
June 26, 1998 |
PCT Filed:
|
December 24, 1996
|
PCT NO:
|
PCT/JP96/03773
|
371 Date:
|
June 25, 1998
|
102(e) Date:
|
June 25, 1998
|
PCT PUB.NO.:
|
WO97/25310 |
PCT PUB. Date:
|
July 17, 1997 |
Foreign Application Priority Data
Current U.S. Class: |
514/237.8; 514/616; 544/169; 544/382; 548/567; 564/139; 564/156 |
Intern'l Class: |
A37G 025/30 |
Field of Search: |
544/169
548/567
564/139
514/237.8
|
References Cited
Foreign Patent Documents |
PCT/JP94/226709 | Nov., 1994 | JP.
| |
Primary Examiner: Ramsuer; Robert W.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt, P.C.
Claims
What is claimed is:
1. A compound of the formula:
##STR9##
wherein R.sup.1 is [di(lower)alkylamino](lower)alkyl,
morpholinyl(lower)alkyl, lower alkylpiperazinyl or [lower
alkylpyrrolidinyl](lower)alkyl,
R.sup.2 is halogen, lower alkyl or lower alkoxy, and
R.sup.3 is halogen, lower alkyl, lower alkoxy or mono(or di or
tri)halo(lower)alkyl,
and a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, wherein
R.sup.1 is [di(lower)alkylamino](lower)alkyl, morpholinyl(lower)alkyl or
[lower alkylpyrrolidinyl](lower)alkyl,
R.sup.2 is halogen, and
R.sup.3 is halogen.
3. A compound of claim 2, wherein
R.sup.1 is [di(lower)alkylamino](lower)alkyl,
R.sup.2 is halogen, and
R.sup.3 is halogen.
4. A compound of claim 3, which is selected from the group consisting of
(1)
[5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]guanidi
ne and
(2)
[5-(2,5-dichlorophenyl)-3-[(2-diethylaminoethyl)-carbamoyl]benzoyl]guanidi
ne,
or a pharmaceutically acceptable salt thereof.
5. A process for preparing a compound of the formula:
##STR10##
wherein R.sup.1 is [di(lower)alkylamino](lower)alkyl,
morpholinyl(lower)alkyl, lower alkylpiperazinyl or [lower
alkylpyrrolidinyl](lower)alkyl,
R.sup.2 is halogen, lower alkyl or lower alkoxy, and
R.sup.3 is halogen, lower alkyl, lower alkoxy or mono(or di or
tri)halo(lower)alkyl,
or a salt thereof, by reacting a compound of the formula
##STR11##
wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, or its
reactive derivative at the carboxy group, or a salt thereof with a
compound of the formula:
##STR12##
or its reactive derivative at the imino group, or a salt thereof.
6. A pharmaceutical composition which comprises, as an active ingredient, a
compound of claim 1 or a pharmaceutically acceptable salt thereof in
admixture with pharmaceutically acceptable carriers.
7. A method for the prophylactic or therapeutic treatment of cardiovascular
diseases, cerebrovascular diseases, renal diseases, arteriosclerosis or
shock which comprises administering a compound of claim 1 or a
pharmaceutically acceptable salt thereof to human being or animals.
8. A process for preparing a pharmaceutical composition which comprises
admixing a compound of claim 1 or a pharmaceutically acceptable salt
thereof with a pharmaceutically acceptable carrier.
9. A method of inhibiting Na.sup.+ /H.sup.+ exchange in mammalian cells,
which comprises administering to a mammal in need thereof an effective
amount of a compound of claim 1 or a pharmaceutically acceptable salt
thereof.
Description
TECHNICAL FIELD
This invention relates to new guanidine derivatives.
One object of this invention is to provide the new and useful guanidine
derivatives and pharmaceutically acceptable salts thereof which possess a
strong inhibitory activity on Na.sup.+ /H.sup.+ exchange in cells.
Another object of this invention is to provide processes for preparation of
the guanidine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical
composition comprising said guanidine derivatives or a pharmaceutically
acceptable salt thereof.
Still further object of this invention is to provide a use of said
guanidine derivatives or a pharmaceutically acceptable salt thereof as a
medicament for the treatment and/or prevention of cardiovascular diseases,
cerebrovascular diseases, renal diseases, arteriosclerosis, shock and the
like in human being and animals.
BACKGROUND ART
Some guanidine derivatives having pharmaceutical activities such as
inhibitory activity on Na.sup.+ /H.sup.+ exchange in cells have been
known as described in WO 94/26709.
DISCLOSURE OF INVENTION
The object guanidine derivatives of the present invention are novel and can
be represented by the following general formula (I):
##STR2##
wherein R.sup.1 is [di(lower)alkylamino](lower)alkyl,
morpholinyl(lower)alkyl, lower alkylpinerazinyl or [lower
alkylpyrrolidinyl](lower)alkyl,
R.sup.2 is halogen, lower alkyl or lower alkoxy, and
R.sup.3 is halogen, lower alkyl, lower alkoxy or mono(or di or
tri)halo(lower)alkyl.
The object compound (I) of the present invention can be prepared by the
following process.
##STR3##
wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above.
The starting compound can be prepared by the following processes or
Preparations mentioned below, or similar manners thereto.
##STR4##
wherein
R.sup.1, R.sup.2 and R.sup.3 are each as defined above,
R.sup.4 is lower alkyl,
R.sup.5 and R.sup.6 are each hydrogen or lower alkyl, and
X.sup.1 and X.sup.2 are each a leaving group.
Suitable pharmaceutically acceptable salts of the object compound (I) are
conventional non-toxic salts and may include a salt with a base or an acid
addition salt such as a salt with an inorganic base, for example, an
alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline
earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium
salt; a salt with an organic base, for example, an organic amine salt
(e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine
salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt
(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic
carboxylic or sulfonic acid addition salt (e.g., formate, acetate,
trifluoroacetate, maleate, tartrate, fumarate, citrate, methanesulfonate,
benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic
amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification,
suitable examples and illustration of the various definitions which the
present invention intends to include within the scope thereof are
explained in detail as follows.
The term "lower" is used to intend a group having 1 to 6, preferably 1 to
4, carbon atom(s), unless otherwise provided.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms
"[di(lower)alkylamino](lower)alkyl", "morpholinyl(lower)alkyl", "lower
alkylpiperazinyl", "[lower alkylpyrrolidinyl](lower)alkyl", "mono(or di or
tri)halo(lower)alkyl" may include straight or branched one having 1 to 6
carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in
which more preferable example may be C.sub.1 -C.sub.4 alkyl.
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and
the like.
Suitable "halogen" and "halogen moiety" in the term "mono(or di or
tri)halo(lower)alkyl" may include fluorine, bromine, chlorine and iodine.
Suitable "leaving group" may include acid residue, lower alkoxy as
exemplified above, and the like.
Suitable "acid residue" may include halogen as exemplified above, acyloxy,
and the like.
Suitable "acyl moiety" in the term "acyloxy" may include Aliphatic acyl
such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl,
butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,
heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,
tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl,
octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher
alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, tert-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.);
mono(or di or tri)halo(lower)alkylsulfonyl (e.g., trifluoromethylsulfonyl,
trichloromethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g.,
methoxysulfonyl, ethoxysulfonyl, etc.); cyclo(lower)alkylcarbonyl (e.g.,
cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); or the like;
Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl,
phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,
phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl,
naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl
[e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl,
phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.),
etc.]; ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g.,
benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl,
naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl (e.g., phenoxyacetyl,
phenoxypropionyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl,
naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl,
p-tolylsulfonyl, etc.); or the like.
Suitable "[di(lower)alkylamino](lower)alkyl" may include
[dimethylamino]methyl, 1-(or 2-)[dimethylamino]ethyl, 1-(or 2- or
3-)[(dimethylamino]propyl, [diethylamino]methyl, 1-(or
2-)[diethylaminolethyl, 1-(or 2- or 3-)[diethylamino]-propyl, and the
like.
Suitable "[lower alkylpyrrolidinyl](lower)alkyl" may include [1-(or 2- or
3- or 4- or 5-)methyl-1-(or 2- or 3-)-pyrrolidinyl]methyl, 1-(or 2-)[1-(or
2- or 3- or 4- or 5-)methyl-1-(or 2- or 3-)pyrrolidinyl]ethyl, 1-(or 2- or
3-)-[1-(or 2- or 3- or 4- or 5-)methyl-1-(or 2- or
3-)-pyrrolidinyl]propyl, [1-(or 2- or 3- or 4- or 5-)ethyl-1-(or 2- or
3-)pyrrolidinyl]methyl, 1-(or 2-)[1-(or 2- or 3- or 4- or 5-)ethyl-1-(or
2- or 3-)pyrrolidinyl]ethyl, 1-(or 2- or 3-)[1-(or 2- or 3- or 4- or
5-)ethyl-1-(or 2- or 3-)-pyrrolidinyl]propyl, and the like.
Suitable "mono(or di or tri)halo(lower)alkyl" may include fluoromethyl,
chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl,
trifluoromethyl, trichloromethyl, tribromomethyl, 1-(or 2-)fluoroethyl,
1-(or 2-)chloroethyl, 1-(or 2-)-bromoethyl, and the like.
Preferred embodiments of the object compound (I) are as follows:
R.sup.1 is [di (lower)alkylamino](lower)alkyl (more preferably
[di(Cl-C.sub.4 alkyl)amino](C.sub.1 -C.sub.4)alkyl, much more preferably
2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 2-(di-ethylamino)ethyl or
3-(diethylamino)propyl, most preferably 2-(dimethylamino)ethyl or
2-(diethylamino)ethyl], morpholinyl(lower)alkyl [more preferably
morpholinyl-(C.sub.1 -C.sub.4)alkyl, much more preferably
2-morpholinoethyl or 3-morpholinopropyl, most preferably
2-norpholinoethyl], or [lower alkylpyrrolidinyl](lower)alkyl [more
preferably [C.sub.1 -C.sub.4 alkylpyrrolidinyl](C.sub.1 -C.sub.4)alkyl,
most preferably 2-(1-methylpyrrolidin-2-yl)ethyl],
R.sup.2 is halogen (more preferably fluorine or chlorine, most preferably
chlorine), lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most
preferably methyl), or lower alkoxy (more preferably C.sub.1 -C.sub.4
alkoxy, most preferably methoxy, and
R.sup.3 is halogen (more preferably fluorine or chlorine, most preferably
chlorine), lower alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most
preferably methyl), lower alkoxy (more preferably C.sub.1 -C.sub.4 alkoxy,
most preferably methoxy), or mono(or di or tri)halo(lower)alkyl [more
preferably mono(or di or tri)halo(Cl-C.sub.4)alkyl, much more preferably
trihalo(C.sub.1 -C.sub.4)alkyl, most preferably trifluoromethyl].
More preferred embodiments of the object compound (I) are as follows
R.sup.1 is [di(lower)alkylamino](lower)alkyl (more preferably [di(C.sub.1
-C.sub.4 alkyl)amino](C.sub.1 -C.sub.4)alkyl, most preferably
2-(dimethylamino)ethyl or 2-(diethylamino)ethyl]),
R.sup.2 is halogen (more preferably chlorine), and
R.sup.3 is halogen (more preferably chlorine).
The processes for preparing the object and starting compounds of the
present invention are explained in detail in the following.
Process (1)
The compound (I) or a salt thereof can be prepared by reacting the compound
(II) or its reactive derivative at the carboxy group, or a salt thereof
with the compound (III) or its reactive derivative at the imino group, or
a salt thereof.
Suitable reactive derivative at the imino group of the compound (III) may
include a silyl derivative formed by the reaction of the compound (III)
with a silyl compound such as bis(trimethylsilyl)acetamide,
mono(trimethylsilyl)acetamide [e.g. N-(trimethylsilyl)acetamide],
bis(trimethylsilyl)urea or the like; a derivative formed by the reaction
of the compound (III) with phosphorus trichloride or phosgene, and the
like.
Suitable reactive derivative at the carboxy group of the compound (II) may
include a conventional one such as an acid halide, an acid anhydride, an
activated amide, an activated ester, and the like.
Suitable examples of the reactive derivatives may be an acid chloride; an
acid azide; a mixed acid anhydride with an acid such as substituted
phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid,
diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric
acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,
sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic
carboxylic acid [e.g. acetic acid, propionic acid, butyric acid,
isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,
2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic
acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated
amide with imidazole, 1-hydroxy-1H-benzotriazole, 4-substituted imidazole,
dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.
cyanomethyl ester, methyl ester, ethyl ester, methoxymethyl ester,
dimethyliminomethyl [(CH.sub.3).sub.2 .dbd.CH--]ester, vinyl ester,
propargyl ester, 2-trifluoromethylsulfonylaminoethyl ester,
2-trifluoromethylsulfonylaminopropyl ester,
2-methyl-2-trifluoromethylsulfonylaminopropyl ester, p-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,
mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl
thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl
thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl
thioester, etc.], or an ester with a N-hydroxy compound [e.g.
N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,
N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,
etc.], and the like. These reactive derivatives can optionally be selected
from them according to the kind of the compound (II) to be used.
The reaction is usually carried out in a conventional solvent such as
water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,
acetonitrile, chloroform, methylene chloride, ethylene chloride,
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any
other organic solvent which does not adversely influence the reaction.
These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound (II) is used in a free acid form or its
salt form, the reaction is preferably carried out in the presence of a
conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N'-carbonyl-bis(2-methylinidazole);
pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine;
ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl
polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride;
lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl
chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxyberzisoxazolium
salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; a combination of
N-lower alkylhalopyridinium halide (e.g., 1-methyl-2-chloropyridinium
iodide, etc.) and tri(lower)alkylamine (e.g. triethylamine, etc.);
so-called Vilsmeier reagent prepared by the reaction of
N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl
chloroformate, phosphorus oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or
organic base such as an alkali metal bicarbonate, tri(lower)alkylamine
(e.g. triethylamine, etc.), pyridine, N-(lower)alkylmorpholine,
N,N-di(lower)alkylbenzylamine, alkali metal lower alkoxide (e.g. sodium
methoxide, etc.) or the like.
The reaction temperature is not critical, and the reaction is usually
carried out under cooling to warming.
Process (A)
The compound (VI) can be prepared by reacting the compound (IV) or a salt
thereof with the compound (V) and then by subjecting the resultant
compound to elimination reaction of lower alkyl.
The reaction can be carried out in the manners disclosed in Preparation 1
or similar manners thereto.
Process (B) The compound (VIIa) or a salt thereof can be prepared by
reacting the compound (VII) or a salt thereof with the compound (VI).
The reaction can be carried out in the manner disclosed in Preparation 4 or
similar manners thereto.
Process (C)
The compound (IIa) or a salt thereof can be prepared by reacting the
compound (VIII) or its reactive derivative at the carboxy group, or a salt
thereof with the compound (IX) or its reactive derivative at the amino
group, or a salt thereof.
This reaction can be carried out in a similar manner to that of the
aforementioned Process (1), and therefore the reagents to be used and the
reaction conditions (e.g., solvent, reaction temperature, etc.) can be
referred to those of the Process (1).
It is to be noted that the object compound (I) may include one or more
stereoisomer(s) due to asymmetric carbon atom(s) and double bond(s) and
all such isomers and mixture thereof are included within the scope of this
invention.
It is further to be noted that isomerization or rearrangement of the object
compound (I) may occur due to the effect of the light, acid, base or the
like, and the compound obtained as the result of said isomerization or
rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g.
hydrate, etc.) and any form of the crystal of the compound (I) are
included within the scope of the present invention.
Regarding the object compound (I), it is to be understood that they include
tautomeric isomers.
That is, a group of the formula:
##STR5##
can be also alternatively represented by its tautomeric formula:
##STR6##
That is, both of the said groups are in the state of equilibrium and such
tautomerism can be represented by that following equilibrium:
##STR7##
And it is obvious to any person skilled in the arts that both of the
tautomeric isomers are easily convertible reciprocally and are included
within the same category of the compound per se.
Accordingly, both of the tautomeric forms of the object compound (I) are
clearly included within the scope of the present invention.
In the present specification, the object compound including the group of
such tautomeric isomers is represented by using one of the expressions
therefor, that is the formula:
##STR8##
only for the convenient sake.
Suitable salts of the object and starting compounds and their reactive
derivatives in Processes (1) and (A).about.(C) can be referred to the ones
as exemplified for the compound (I).
The new guanidine derivatives (I) and a pharmaceutically acceptable salt
thereof of the present invention possess a strong inhibitory activity on
Na.sup.+ /H.sup.+ exchange in cells and therefore are useful as an
inhibitor on Na.sup.+ /H.sup.+ exchange in cells.
Accordingly, the new guanidine derivatives (I) and a pharmaceutically
acceptable salt thereof can be used for the expectorant and for the
treatment and/or prevention of cardiovascular diseases [e.g. hypertension,
angina pectoris, myocardial infarction, heart failure (e.g. congestive
heart failure, acute heart failure, cardiac hypertrophy, etc.), arrhythmia
(e.g. ischenic arrhythmia, arrhythmia due to myocardial infarction,
arrhythmia after PTCA or after thrombolysis, etc.), restenosis after PTCA,
etc.], cerebrovascular diseases [e.g. ischemic stroke, hemorrhagic stroke,
etc.], renal diseases [e.g. diabetic nephropathy, ischemic acute renal
failure, etc.], arteriosclerosis, shock [e.g. hemorrhagic shock, endotoxin
shock, etc.] and the like, and can also be used as an agent for ischemic
reperfusion injury, myocardial protection, organ protection in organ
transplantation, open heart surgery, and the like.
In order to show the utilities of the guanidine derivatives (I) and a
pharmaceutically acceptable salt thereof of the present invention,
pharmacological test data of the representative compound of the guanidine
derivatives (I) are illustrated in the following.
[1] Test Compound
(a)
[5-(2,5-dichlorophenyl)-3-[(2-morpholinoethyl)-carbamoyl]benzoyl]guanidine
.dihydrochloride
[2] Inhibitory activity on Na.sup.+ /H.sup.+ exchange in cells
[i] Test Method
Procedure was carried out according to a similar manner to the method
described in Enzymology 173 , 777 (1989).
Cell Preparation
One male SD strain rat weighing 250-300 g was sacrificed with the blow on
the head. Then, the thymus was removed into ice-cold NaCl medium (140 mM
sodium chloride, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM
magnesium chloride, 10 mM glucose and 20 mM
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEADS)--pH 7.3), cut
in small fragments, and transferred to glass homogenizer. The cells were
dissociated by gentle strokes, and the resulting suspension was filtrated
through six layers of surgical gauze and the filtrate was centrifuged at
4.degree. C. at 1000 g for 5 minutes. The pellet was resuspended in RPMI
1640 medium (pH 7.3) at room temperature to adjust final cell
concentration (1.times.10.sup.7 cells/ml).
Assay
This method detects the swelling that accompanies activation of Na.sup.+
/H.sup.+ exchanger in cells incubated with sodium propionate. Propionic
acid rapidly penetrates through the membrane. Intracellular dissociation
brings about cytoplasmic acidification and consequently activation of
Na.sup.+ /H.sup.+ exchanger, which exchange extracellular Na.sup.+ for
cytoplasmic H.sup.+. The uptake of osmotically obliged water was
manifested as cell swelling.
Cell sizing and counting were performed electrically with the Coulter
Counter-Channelyzer (AT-II). 0.1 ml Thymocytes solution were suspended in
20 ml sodium-propionate medium (140 mM sodium propionate, 1 mM potassium
chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose,
20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)--pH 6.8)
including test compound solved in dimethyl sulfoxide (final concentration
of dimethyl sulfoxide was 0.1%). During 4 minutes, increase of cell volume
induced by Na.sup.+ /H.sup.+ exchanger was kept linear, and the time
course of swelling was observed each minute after the addition of
thymocytes. Rate of Swelling (.DELTA. volume/min.) was measured by using
3-5 concentrations of test compound. Then, apparent Ki value of test
compound was calculated by using Line weaver-Burk plot.
[3] Test Result:
______________________________________
Test Compound Ki (M)
______________________________________
(a) <1.0 .times. 10.sup.-7
______________________________________
The object compound (I) or its pharmaceutically acceptable salts can
usually be administered to mammals including human being in the form of a
conventional pharmaceutical composition such as oral dosage form (e.g.,
capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol,
inhalation, suspension, emulsion, etc.), injection dosage form,
suppository, ointment, or the like.
The pharmaceutical composition of this invention can contain various
organic or inorganic carrier materials, which are conventionally used for
pharmaceutical purpose such as excipient (e.g., sucrose, starch, mannit,
sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium
carbonate, etc.), binding agent (e.g., cellulose, methyl cellulose,
hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic,
polyethyleneglycol, sucrose, starch, etc.), disintegrator (,e.g., starch,
carboxymethyl cellulose, calcium salt of carboxymethyl cellulose,
hydroxypropylstarch, sodium glycolestarch, sodium bicarbonate, calcium
phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate,
talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid,
mentol, glycine, orange powders, etc.), preservative (e.g., sodium
benzoate, sodium bisulfite, methylparaben, propylparaben, etc.),
stabilizer (e.g., citric acid, sodium citrate, acetic acid, etc.),
suspending agent (e.g., methyl cellulose, polyvinylpyrrolidone, aluminum
stearate, etc.), dispersing agent, aqueous diluting agent (e.g., water,
etc.), base wax (e.g., cacao butter, polyethyleneglycol, white petrolatum,
etc.).
The effective ingredient may usually be administered with a unit dose of
0.01 mg/kg to 500 mg/kg, 1 to 4 times a day. However, the above dosage may
be increased or decreased according to age, weight, conditions of the
patient or the administering method.
The following Preparations and Examples are given for the purpose of
illustrating the present invention in more detail.
Preparation 1
To a cold (-78.degree. C.) solution of 2,5-dichloroiodobenzene (50 g) and
triisopropoxyborane (46.5 ml) in tetrahydrofuran (500 ml) was added
dropwise n-butyllithium in hexane (1.69 M, 119 ml). The mixture was
stirred at -78.degree. C. for 30 minutes. The reaction mixture was poured
into 2M hydrochloric acid solution (180 ml) and stirred for 10 minutes.
The product was extracted with ether (200 ml) 2 times, and the organic
layers were combined, washed with brine, dried over magnesium sulfate and
evaporated in vacuo. To the residue was added n-hexane (60 ml) and the
crystalline was collected, washed with n-hexane and dried to give
2,5-dichlorophenyl-dihydroxyborane (21.0 g).
mp: 219-220.degree. C.
IR (Nujol): 1580, 1155, 1000, 820 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 7.3-7.5 (3H, m)
Preparation 2
The following compounds were obtained according to a similar manner to that
of Preparation 1.
(1) 2,5-Dimethoxyphenyl-dihydroxyborane
mp: 96-98.degree. C.
IR (Nujol): 1610, 1585, 1570, 1215, 730 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.70 (3H, s), 3.77 (3H, s), 6.88-6.99 (2H, m),
7.12-7.14 (1H, m), 7.75 (2H, s)
(2) 2,5-Difluorophenyl-dihydroxyborane
mp: 239-241.degree. C.
IR (Nujol): 3300 (br), 1620, 1120 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 7.08-7.33 (3H, m), 8.30 (2H, br s)
(3) 5-Chloro-2-methylphenyl-dihydroxyborane
mp: 184-186.degree. C.
IR (Nujol): 1590, 1400, 1340 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.62 (3H, s), 7.19 (1H, d, J=8.2 Hz), 7.30
(1H, dd, J=8.2, 2.4 Hz), 7.79 (1H, d, J=2.4 Hz)
(4) 2-Chloro-5-methylphenyl-dihydroxyborane
mp: 101-103.degree. C.
IR (Nujol): 3270, 1730, 1630, 1590, 1340 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.26 (3H., s), 7.13 (1H, dd, J=8.0, 1.9 Hz),
7.20 (1H, d, J=1.9 Hz), 7.22 (1H, d, J=8.0 Hz), 8.26 (2H, s)
(5) 2-Chloro-5-trifluoromethylphenyl-dihydroxyborane
mp: 175-177.degree. C.
IR (Nujol): 3350, 1600, 1580, 1320 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 7.61 (1H, d, J=8.2 Hz), 7.68-7.74 (2H, s)
(6) 5-Chloro-2-methoxyphenyl-dihydroxyborane
mp: 145-147.degree. C.
IR (Nujol): 3400, 1590, 1570, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.79 (3H, s), 7.00 (1H, d, J=8.7 Hz), 7.38
(1H, d, J=2.8 Hz), 7.44 (1H, d, J=8.7, 2.8 Hz), 7.87 (2H, s)
Preparation 3
To a mixture of 2-chloro-5-methoxyphenol (3.0 g), 2,6-lutidine (2.64 ml)
and 4-dimethylaminopyridine (0.356 g) in 1,2-dichloroethane (60 ml) was
added dropwise bis(trifluoromethanesulfonic)anhydride (3.82 ml) at
-30.degree. C. over 10 minutes. The mixture was stirred at -30.degree. C.
for 30 minutes and then was warmed to room temperature. After 2 hours,
water was added to the reaction mixture and two layers were separated. The
organic layer was dried over magnesium sulfate and evaporated in vacuo.
The residue was dissolved in ethyl acetate (60 ml) and was washed
successively with 10% hydrochloric acid solution, water, sodium
hydrogencarbonate solution and brine. The organic layer was dried over
magnesium sulfate and evaporated in vacuo to give
2-chloro-5-methoxy-1-trifluoromethylsulfonyloxybenzene (4.99 g, 90.8%).
IR (Neat): 1600, 1580, 1490, 1220, 1140 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.83 (3H, s), 7.14 (1H, dd, J=8.9, 2.9 Hz),
7.20 (1H, d, J=2.9 Hz), 7.68 (1H, d, J=8.9 Hz)
Preparation 4
The mixture of 2,5-dichlorophenyl-dihydroxyborane (9.35 g),
5-methoxycarbonyl-3-iodobenzoic acid (10 g), potassium carbonate (14.0 g)
and palladium(II) acetate (0.073 g) in water (200 ml) was stirred at
40.degree. C. for four hours. Undissolved material was filtered, washed
with water (100 ml), suspended in water (150 ml) and adjusted to pH 2.0
with 6N hydrochloric acid. The mixture was extracted two times with a
mixture of ethyl acetate (120 ml) and tetrahydrofuran (60 ml), washed with
brine, dried over magnesium sulfate and evaporated in vacuo. The residual
crystalline was washed with n-hexane to give
3-methoxycarbonyl-5-(2,5-dichlorophenyl)benzoic acid (5.36 g, 50.4%).
mp: 222-224.degree. C.
IR (Nujol): 1730, 1710, 1600, 1140, 1100, 1040 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.92 (3H, s), 7.5-7.7 (3H, m), 8.22 (2H, S),
8.53 (1H, s), 13.53 (1H, s)
(+) APCI MASS: 325 [M+H.sup.+, 327 [M+H].sup.+
Preparation 5
The following compound was obtained according to a similar manner to that
of Preparation 4.
5-(2,5-Dimethoxyphenyl)-3-methoxycarbonylbenzoic acid
mp: 212-214.degree. C.
IR (Nujol): 1730, 1690, 1500, 1265, 1040, 720 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.77 (3H, s), 3.91 (3H, s), 6.95
(1H, d, J=3.0 Hz), 6.99 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.10 (1H, d, J=8.7
Hz), 8.22-8.27 (2H, m), 8.43-8.46 (1H, m), 13.40 (1H, br)
(+) APCI MASS: 317 [M+H].sup.+
Preparation 6
A mixture of methyl
3-((2-dimethylaminoethyl)carbamoyl]-5-(trifluoromethylsulfonyloxy)benzoate
(2 g), 2,5-dichlorophenyl-dihydroxyborane 1.25 g),
tetrakis(triphenylphosphine)palladium(0) (0.17 g) and triethylamine (1.52
g) in N,N-dimethylformamide (40 ml) was heated at 100.degree. C. for 3
hours under nitrogen atmosphere. After evaporating the solvent, the
residue was dissolved in a mixture of ethyl acetate (100 ml) and water
(100 ml). The organic layer was successively washed with 10% potassium
carbonate aqueous solution, brine and dried over magnesium sulfate. The
solvent was evaporated in vacuo and the residue was purified by column
chromatography on silica gel (100 ml) eluting with a mixture of chloroform
and methanol (20:1). The fractions containing the desired products were
collected and evaporated in vacuo. The residue was crystallized from
diisopropyl ether to afford methyl
5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.
mp: 104-105.degree. C.
IR (Nujol): 3250, 1730, 1640, 1160, 730 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.18 (6H, s), 2.42 (2H, t, J=6.8 Hz), 3.40
(2H, dt, J=6.8, 5.5 Hz), 3.92 (3H, s), 7.55 (1H, dd, J=8.4, 2.6 Hz), 7.64
(1H, d, J=2.6 Hz), 7.66 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.6, 1.6 Hz),
8.18 (1H, dd, J=1.6, 1.6 Hz), 8.50 (1H, dd, J=1.6, 1.6 Hz), 8.70 (1H, t,
J=5.5 Hz)
(+) APCI MASS: 395 [M+H].sup.+, 397 [M+H].sup.+
Preparation 7
The following compounds were obtained according to a similar manner to that
of Preparation 6.
(1) Methyl 5-(2,5-difluorophenyl)-3-[(2-dimethylaminoethyl)
carbamoyl]benzoate.hydrochloride
mp: 164-165.degree. C.
IR (Nujol): 3300, 1730, 1660, 1530, 1260 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.83 (6H, s), 3.28-3.38 (2H, m), 3.67-3.79
(2H, m), 3.93 (3H, s), 7.31-7.52 (2H, m), 7.64-7.74 (1H, m), 8.29 (1H, s),
8.43 (1H, s), 3.51 (1H, s), 9.26 (1H, t, J=5.3 Hz), 10.45 (1H, br s)
(+) APCI MASS: 363 [M+H].sup.+
(2) Methyl 5-(5-chloro-2-methylphenyl)-3-[(2-dimethylaminoethyl)
carbamoyl]benzoate.hydrochloride
mp: 170-173.degree. C.
IR (Nujol): 1730, 1640, 1540, 1260 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.21 (3H, s), 2.82 (6H, s), 3.25-3.37 (2H, m),
3.65-3.75 (2H, m), 3.91 (3H, s), 7.37-7.45 (3H, m), 8.04 (1H, dd, J=1.5,
1.5 Hz), 8.18 (1:H, dd, J=1.5, 1.5 Hz), 8.50 (1H, dd, J=1.5, 1.5 Hz), 9.13
(1H, J=5.3 Hz), 10.25 (1H, br s)
(+) APCI MASS: 375 [M+H].sup.+, 377 [M+H.sup.+
(3) Methyl
5-(2-chloro-5-methylphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.hy
drochloride
mp: 135-137.degree. C.
IR (Nujol): 3250, 1720, 1660, 1530, 1270 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.37 (3H, s), 2.82 (6H, s), 3.25-3.37 (2H, m),
3.64-3.77 (2H, m), 3.92 (3H, s), 7.29 (1H, dd, J=8.1, 1.7 Hz), 7.39 (1H,
d, J=1.7 Hz), 7.50 (1H, d, J=8.1 Hz), 8.15 (1H, dd, J=1.6, 1.6 Hz), 8.26
(1H, dd, J=1.6, 1.6 Hz), 8.52 (1H, dd, J=1.6, 1.6 Hz), 9.14 (1H, t, J=5.5
Hz), 10.41 (1H, br s)
(+) APCI MASS: 375 [M+H].sup.+, 377 [M+H].sup.+
(4) Methyl
5-(2-chloro-5-trifluoromethylphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]be
nzoate.hydrochloride
mp: 190-192.degree. C.
IR (Nujol): 1730, 1650, 1540, 1260 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.82 (6H, s), 3.25-3.37 (2H, m), 3.64-3.78
(2H, m), 3.92 (3H, s), 7.85-7.95 (3H, m), 8.21 (1H, dd, J=1.6, 1.6 Hz),
8.32 (1H, dd, J=1.6, 1.6 Hz), 8.56 (1H, dd, J=1.6, 1.6 Hz), 9.21 (1H, t,
J=5.4 Hz), 10.49 (1H, br s)
(+) APCI MASS: 429 [M+H].sup.+, 431 [M+H].sup.+
(5) Methyl 5-(5-chloro-2-nethoxyphenyl) -3-
(2-dimethylaminoethyl)carbamoyl]benzoate.hydrochloride
mp: 196-198.degree. C.
IR (Nujol): 3250, 1720, 1650, 1520, 1250 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.82 (6H, s), 3.25-3.35 (2H, m), 3.65-3.75
(2H, m), 3.80 (3H, s), 3.91 (3H, s), 7.20 (1H, d, J=8.6 Hz), 7.47 (1H, dd,
J=8.6, 2.6 Hz), 7.51 (1H, d, J=2.6 Hz), 8.22 (1H, dd, J=1.6, 1.6 Hz), 8.28
(1H, dd, J=1.6, 1.6 Hz), 8.46 (1H, dd, J=1.6, 1.6 Hz), 9.13 (1H, J=5.4
Hz), 10.43 (1H, br s)
(+) APCI MASS: 391 [M+H].sup.+, 393 [M+H].sup.+
(6) Methyl
5-(2,5-dimethylphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate
IR (Film): 3250, 1720, 1035 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.19 (6H, s), 2.44 (2H, t, J=6.8 Hz), 3.3-3.5
(2H, m), 3.91 (3H, s), 7.05-7.25 (3H, m), 7.98 (1H, s), 8.09 (1H, s), 8.45
(1H, s), 8.72 (1H, t, J=5.4 Hz)
Preparation 8
A mixture of 2-chloro-5-methoxy-1-trifluoromethyl-sulfonyloxybenzene (0.30
g), 3,5-dimethoxycarbonylphenyl-dihydroxyborane (0.32 g), triethylamine
(0.43 ml) and tetrakis(triphenylphosphine)palladium(0) (0.036 g) in
N,N-dimethylformamide (6 ml) was heated at 100.degree. C. for 3 hours
under nitrogen atmosphere. The reaction mixture was poured into water (30
ml) and the product was extracted with ethyl acetate (30 ml). The organic
layer was successively washed with water, potassium carbonate solution,
hydrochloric acid solution and brine, and was dried over magnesium
sulfate. The solvent was removed under reduced pressure. The residue was
triturated with diethyl ether and the product was collected by filtration,
washed with diethyl ether to afford dimethyl
5-(2-chloro-5-methoxyphenyl)isophthalate.
mp: 152-154.degree. C.
IR (Nujol): 1720, 1590, 1300, 1240 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.81 (3H, s), 3.92 (6H, s), 7.02-7.10 (2H, m),
7.49-7.54 (1H, m), 8.22 (2H, d, J=1.6 Hz), 8.51 (1H, dd, J=1.6, 1.6 Hz)
(+) APCI MASS: 335 [M.revreaction.H]+, 337 [M+H].sup.+
Preparation 9
A mixture of dimethyl 5-(2-chloro-5-methoxyphenyl)-isophthalate (1.20 g)
and potassium hydroxide (0.23 g) in methanol (60 ml) and 1,4-dioxane (20
ml) was refluxed for 48 hours. The mixture was evaporated in vacuo and to
the residue was added ethyl acetate and water. Two layers were separated
and the aqueous layer was acidified with hydrochloric acid solution. The
product was extracted with ethyl acetate and the organic layer was washed
with water and brine, dried over magnesium sulfate and evaporated in vacuo
to give 5-(2-chloro-5-methoxyphenyl)-3-methoxycarbonylbenzoic acid (0.96
g, 83.5%).
mp: 214-216.degree. C.
IR (Nujol): 1720, 1690, 1590, 1220 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.82 (3H, s), 3.92 (1H, s), 7.02-7.07 (2H, m),
7.52 (1H, d, J=9.2 Hz), 8.18 (1H, dd, J=1.6, 1.6 Hz), 8.21 (1H, dd, J=1.6,
1.6 Hz), 8.51 (1H, dd, J=1.6, 1.6 Hz), 13.45 (1H, br s)
(+) APCI MASS: 321 [M+H].sup.+
Preparation 10
To a mixture of 3-methoxycarbonyl-5-(2,5-dichlorophenyl)benzoic acid (1.0
g), N,N-dimethylethylenediamine (0.223 g) and 1-hydroxybenzotriazole
(0.376 g) in N,N-dimethylformamide (10 ml) was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.533 g) under ice cooling,
and then the solution was stirred for five hours at room temperature.
After evaporating the solvent, the residue was dissolved in a mixture of
ethyl acetate (50 ml) and water (50 ml) and adjusted to pH 10 with 6N
aqueous potassium carbonate solution with stirring. The organic layer was
washed with brine, dried over magnesium sulfate and evaporated in vacuo.
The residue was purified by column chromatography on silica gel (100 ml)
eluting with a mixture of chloroform and methanol (20:1). The fractions
containing the desired product were collected and evaporated in vacuo. The
residue was dissolved in ethanol (8 ml) and added slightly excess 4N
hydrogen chloride in dioxane to afford methyl
5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl)benzoate.hydroch
loride (0.43 g).
mp: 213-216.degree. C.
IR (Nujol): 1730, 1655, 1520, 1260, 1235, 1095 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.82 (6H, s), 3.29 (2H, t, J=5.7 Hz), 3.69
(2H, t, d, J=5.7 Hz, 5.2 Hz), 3.92 (3H, s), 7.56 (1H, dd, J=8.6, 2.3 Hz),
7.66 (1H, d, J=8.6 Hz), 7.68 (1H, d, J=2.3 Hz), 8.18 (1H, s), 8.29 (1H,
s), 8.54 (1H, s), 9.20 (1H, t, J=5.2 Hz), 10.52 (1H, s)
(+) APCI MASS: 395 [M+H].sup.+, 397 [M+H].sup.+
Preparation 11
The following compounds were obtained according to a similar manner to that
of Preparation 10.
(1) Methyl
5-(2,5-dichlorophenyl)-3-(4-methylpiperazin-1-ylcarbamoyl)benzoate
mp: 220-222.degree. C. (dec.)
IR (Nujol): 3200, 1720, 1640, 1330, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.19 (3H, s), 2.35-2.50 (4H, m), 2.89 (4H, t,
J=4.6 Hz), 3.91 (3H, s), 7.56 (1H, dd, J=8.8, 2.2 Hz), 7.65 (1H, d, J=2.2
Hz), 7.67 (1H, d, J=8.8 Hz), 8.10 (1H, dd, J=1.6, 1.6 Hz), 8.13 (1H, dd,
J=1.6, 1.6 Hz), 8.42 (1H, dd, J=1.6, 1.6 Hz), 9.69 (1H, s)
(+) APCI MASS: 422 [M+H].sup.+, 424 [M+H].sup.+
(2) Methyl
5-(2,5-dichlorophenyl)-3-[(2-diethylaminoethyl)-carbamoyl]benzoate
IR (Neat): 3300, 1720, 1650, 1540, 1260 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 0.97 (6H, t, J=7.1 Hz), 2.45-2.65 (6H, m),
3.30-3.42 (2H, m), 3.92 (3H, s), 7.56 (1H, dd, J=8.5, 2.6 Hz), 7.65 (1H,
d, J=2.6 Hz), .sup.7.67 (1H, d, J=8.5 Hz), 8.14 (1H, dd, J=1.6, 1.0 Hz),
8.17 (1H, dd, J=1.6, 1.6 Hz, 8.49 (1H, dd, J=1.6, 1.6Hz), 8.71 (1H, t,
J=5.5 Hz)
(+) APCI MASS: 423 [M+H].sup.+, 425 [M+H].sup.+
(3) Methyl 5-(2,5-dichlorophenyl)-3-[(.sup.3
-diethylaminopropyl)-carbamoyl]benzoate
IR (Neat): 3300 (br), 1720, 1650, 1540 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 0.95 (6H, t, J=7.1 Hz), 1.62-1.78 (2H, m),
2.42-2.58 (6H, m), 3.27-3.40 (2H, m), 3.92 (3H, s), 7.55 (1H, dd, J=8.6,
2.6 Hz), 7.64 (1H, d, J=2.6 Hz), 7.67 (1H, dd, J=8.6 Hz), 8.14 (1H, dd,
J=1.6, 1.6 Hz), 8.18 (1H, dd, J=1.6, 1.6 Hz), 8.49 (1H, dd, J=1.6, 1.6
Hz), 8.85 (1H, t, J=5.2 Hz)
(+) APCI MASS: 437 [M+H].sup.+, 439 [M+H].sup.+
(4) Methyl
5-(2,5-dichlorophenyl)-3-[(3-morpholinopropyl)-carbamoyl]benzoate
mp: 101-103.degree. C.
IR (Nujol): 3250, 1720, 1630, 1550, 1260, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.65-1.80 (2H, m), 2.30-2.42 (6H, m),
3.28-3.42 (2H, m), 3.56 (4H, t, J=4.5 Hz), 3.92 (3H, s), 7.55 (1H, dd,
J=8.5, 2.5 Hz), 7.64 (1H, d, J=2.5 Hz), 7.67 (1H, d, J=8.5 Hz), 8.14 (1H,
dd, J=1.5, 1.5 Hz), 8.18 (1H, dd, J=1.5, 1.5 Hz), 8.50 (1H, dd, J=1.5, 1.5
Hz), 8.78 (1H, t, J=5.4 Hz)
(+) APCI MASS: 451 [M+H].sup.+, 453 [M+H].sup.+
(5) Methyl
5-(2,5-dichlorophenyl)-3-[[2-(1-methylpyrrolidin-2-yl)ethyl]carbamoyl]benz
oate
mp: 97-100.degree. C.
IR (Nujol): 3250, 1720, 1630, 1530, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.38-1.72 (4H, m), 1.82-2.20 (4H, m), 2.23
(3H, s), 2.90-3.02 (1H, m), 3.30-3.43 (2H, m), 3.92 (3H, s), 7.56 (1H, dd,
J=8.6, 2.6 Hz), 7.65 (1H, d, J=2.6 Hz), 7.67 (1H, d, J=8.6 Hz), 8.14 (1H,
dd, J=1.6, 1.6 Hz, 8.17 (1H, dd, J=1.6, 1.6 Hz), 8.49 (1H, dd, J=1.6, 1.6
Hz), 8.82 (1H, t, J=5.4 Hz)
(+) APCI MASS: 435 [M+H].sup.+, 437 [M+H].sup.+
(6) Methyl
5-(2-chloro-5-nethoxyphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.h
ydrochloride
mp: 140-142.degree. C.
IR (Nujol): 3250, 1710, 1650, 1590, 1550, 1270 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.82 (6H, s), 3.28-3.38 (2H, m), 3.62-3.75
(2H, m), 3.84 (3H, s), 3.92 (3H, s), 7.05 (1H, dd, J=8.8, 3.0 Hz), 7.13
(1H, d, J=3.0 Hz), 7.51 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=1.6, 1.6 Hz),
8.30 (1H, dd, J=1.6, 1.6 Hz), 8.52 (1H, dd, J=1.6, 1.6 Hz), 9.22 (1H, t,
J=5.4 Hz), 10.53 (1H, br s)
(+) APCI MASS: 391 [M+H].sup.+, 393 [M+H].sup.+
(7) Methyl 5-(2,5-dichlorophenyl)-3-[(2-morpholinoethyl)-carbamoyl]benzoate
IR (Film): 1720, 1655, 910, 755 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.35-2.50 (4H, m), 2.5-2.6 (2H, m), 3.35-3.50
(2H, m), 3.5-3.65 (4H, m), 3.92 (3H, s), 7.56 (1H, dd, J=8.4, 2.7 Hz),
7.65 (1H, d, J=2.7 Hz), 7.67 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.6, 1.6
Hz), 8.18 (1H, da, J=1.6, 1.6 Hz), 8.49 (1H, dd, j=1.6, 1.6 Hz), 8.73 (1H,
t, J=5.5 Hz)
(+) APCI MASS: 437 [M+H].sup.+, 439 [M+H].sup.+
(8) Methyl
5-(2,5-dichlorophenyl)-3-[(3-dimethylaminopropyl)carbamoyl]benzoate
IR (Film) 3275, 1720, 1100, 1040, 880, 810 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.) 2.14 (6H, s), 1.55-1.75 (2H, m), 2.27 (2H, t,
J=7.0 Hz), 3.25-3.35 (2H, m), 3.91 (3H, s), 7.56 (1H, dd, J=8.3, 2.7 Hz),
7.66 (1H, s) 8.14 (1H, dd, J=2.0, 2.0 Hz), 8.16 (1H, dd, J=2.0, 2.0 Hz),
8.49 (1H, dd, J=2.0, 2.0 Hz), 8.83 (1H, t, J=5.6 Hz)
(+) APCI MASS: 409 [M+H].sup.+, 411 [M+H].sup.+
(9) Methyl
5-(2,5-dimethoxyphenyl)-3-((2-dimethylaminoethyl)carbamoyl]benzoate.hydroc
hloride
mp: 175-177.degree. C.
IR (Nujol): 3250, 1710, 1650, 1595, 1040, 715 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.81 (3H, s), 2.84 (3H, s), 3.25-3.40 (2H, m),
3.60-3.80 (2H, m), 3.73 (3H, s), 3.79 (3H, s), 3.91 (3H, s), 6.95-7.15
(3H, m), 8.22 (1H, dd, J=1.6, 1.6 Hz), 8.30 (1H, dd, J=1.6, 1.6 Hz), 8.44
(1H, dd, J=1.6, 1.6 Hz) 9.15 (1H, t, J=5.4 Hz), 10.45 (1H, br s)
(+) APCI MASS: 387 [M+H].sup.+
EXAMPLE 1
To a solution of guanidine.hydrochloride (0.4 g) in N,N-dimethylformamide
(7.2 ml) was added sodium methoxide (0.76 ml, 28% in methanol) under
nitrogen atmosphere. After being stirred for 15 minutes at room
temperature, to the reaction mixture was added methyl
5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.hydroch
loride (0.36 g). After being stirred for 4 hours at room temperature, the
residue was dissolved in a mixture of ethyl acetate (40 ml),
tetrahydrofuran (20 ml) and water (40 ml). The aqueous layer was further
extracted with a mixture of ethyl acetate (40 ml) and tetrahydrofuran (20
ml). The combined organic layer was washed with brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was dissolved in
ethanol (8 ml) and added slightly excess 4N hydrochloride in dioxane to
afford
[5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]guanidi
ne.dihydrochloride.
mp: 224-227.degree. C.
IR (Nujol): 3275, 1710, 1640, 1230, 1120, 870 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.83 (1H, s), 3.25-3.45 (2H, m), 3.70 (2H, td,
J=5.7, 5.2 Hz), 7.55 (1H, dd, J=8.6, 2.3 Hz), 7.67 (1H, d, J=8.6 Hz), 7.78
(1H, d, J=2.3 Hz), 8.32 (1H, s), 8.41 (1H, s), 8.70 (1H, s), 8.6-8.9 (4H,
s), 9.18 (1H, t, J=5.2 Hz), 10.41 (1H, br s), 12.38 (1H, s)
(+) APCI MASS: 422 [M+H].sup.+, 424 [M+H].sup.+
EXAMPLE 2
The following compounds were obtained according to a similar manner to that
of Example 1.
(1) [5-(2,
5-Dichlorophenyl)-3-(4-methylpiperazin-1-ylcarbamoyl)benzoyl]guanidine.dih
ydrochloride
mp: 239-241.degree. C.
IR (Nujol): 3150, 1710, 1670, 1260 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.78 (3H, s), 3.10-3.50 (8H, m), 7.57 (1H, dd,
J=8.6, 2.4 Hz), 7.68 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=2.4 Hz), 8.20 (1H,
s), 8.36 (1H, S), 8.62 (1H, s), 8.72 (4H, s), 10.09 (1H, s), 10.89 (1H, br
s), 12.36 (1H, s)
(+) APCI MASS: 449 [M+H].sup.+, 451 [M+H.sup.+
(2)
(5-(2,5-Dichlorophenyl)-3-[(2-diethylaminoethyl)-carbamoyl]benzoyl]guanidi
ne.dihydrochloride
mp: 230-232.degree. C.
IR (Nujol): 3300, 1710, 1690, 1660, 1540, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.24 (6H, t, J=7.1 Hz), 3.15-3.38 (6H, m),
3.68-3.80 (2H, m), 7.58 (1H, dd, J=8.6, 2.5 Hz), 7.69 (1H, d, J=8.6 Hz),
7.77 (1H, d, J=2.5 Hz), 8.31 (1H, s), 8.39 (1H, s), 8.68 (1H, s), 8.70
(4H, s), 9.19 (1H, t, J=5.4 Hz), 10.31 (1H, br s), 12.29 (1H, s)
(+) APCI MASS: 450 [M+H].sup.+, 452 [M+H].sup.+
(3)
[5-(2,5-Dichlorophenyl)-3-[(3-morpholinopropyl)-carbamoyl]benzoyl]guanidin
e.dihydrochloride
mp: 203-205.degree. C.
IR (Nujol): 3300, 1700, 1650, 1250 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.95-2.13 (2H, m), 2.97-3.30 (4H, m),
3.38-3.50 (4H, m), 3.70-3.87 (2H, m), 3.90-4.03 (2H, m), 7.57 (1H, dd,
J=8.6, 2.5 Hz), 7.69 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=2.5 Hz), 8.24 (1H,
s), 8.33 (1H, s), 8.70 (1H, s), 8.70 (4H, s), 8.95 (1H, t, J=5.4 Hz),
10.90 (1H, br s), 12.33 (1H, s)
(+) APCI MASS: 478 [M+H]+, 480 [M+H]+(4)
[5-(2,5-Dichlorophenyl)-3-[[2-(1-methylpyrrolidin-2-yl)ethyl]carbamoyl]ben
zoyl]guanidine.dihydrochloride
mp: 210-213.degree. C.
IR (Nujol): 3300, 1710, 1640, 1530, 1260,1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.62-2.10 (4H, m), 2.15-2.43 (4H, m), 2.78
(3H, S), 2.95-3.17 (1H, m), 3.33-3.62 (4H, m), 7.57 (1H, dd, J=8.6, 2.5
Hz), 7.69 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=2.5 Hz), 8.24 (1H, s), 8.33
(1H, s), 8.70 (1H, s), 8.71 (4H, s), 8.92 (1H, t, J=5.4 Hz), 10.60 (1H, br
s), 12.36 (1H, s)
(+) APCI MASS: 462 [M+H].sup.+, 464 [M+H].sup.+
(5)
[5-(2,5-Difluorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]guanidi
ne.dihydrochloride
mp: 213-215.degree. C.
IR (Nujol): 3400 (br), 1720, 1650, 1580, 1540, 1260 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.84 (6H, s), 3.28-3.40 (2H, m), 3.65-3.78
(2H, m), 7.32-7.53 (2H, m), 7.79-7.88 (1H, m), 8.44 (1H, s), 8.54 (1H, s),
8.65 (1H, s), 8.76 (4H, s), 9.24 (1H, t, J=5.2 Hz), 10.37 (1H, br s),
12.44 (1H, s)
(+) APCI MASS: 390 [M+H].sup.+
(6)
[5-(5-Chloro-2-methylphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]gu
anidine.dihydrochloride
mp: 219-221.degree. C.
IR (Nujol): 3300, 1710, 1700, 1640, 1550, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.27 (3H, s), 2.83 (6H, s), 3.27-3.39 (2H, m),
3.65-3.75 (2H, m), 7.38-7.50 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.63
(1H, s), 8.78 (4H, s), 9.17 (1H, t, J=5.3 Hz), 10.41 (1H, br s), 12.33
(1H, s)
(+) APCI MASS: 402 [M+H].sup.+, 404 [M+H].sup.+
(7)
[5-(2-Chloro-5-methylphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]gu
anidine.dihydrochloride
mp: 167-169.degree. C.
IR (Nujol): 3300, 1710, 1690, 1550, 1260, 1230 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.37 (3H, s), 2.84 (6H, s), 3.28-3.38 (2H, m),
3.63-3.77 (2H, m), 7.29 (1H, dd, J=8.1, 1.9 Hz), 7.50 (1H, d, J=8.1 Hz),
7.51 (1H, d, J=1.9 Hz), 8.29 (1H, s), 8.36 (1H, s), 8.69 (1H, s), 8.75
(4H, s), 9.12 (1H, t, J=5.4 Hz), 10.37 (1, br s), 12.30 (1H, s)
(+) APCI MASS: 402 [M+H].sup.+, 404 [M+H.sup.+
(8)
[5-(2-Chloro-5-trifluorormethylphenyl)-3-[(2-dimethyl-aminoethyl)carbamoyl
]benzoyl]guanidine.dihydrochloride
mp: 170-172.degree. C.
IR (Nujol): 3300, 1720, 1640, 1570, 1320 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.84 (6H, s), 3.28-3.38 (2H, m), 3.65-3.75
(2H, m), 7.84-7.94 (2H, m), 8.01 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 8.72
(1H, s), 8.73 (4H, s), 9.14 (1H, t, J=5.4 Hz), 10.31 (1H, br s), 12.36
(1H, s)
(+) APCI MASS: 456 [M+H].sup.+, 458 [M+H].sup.+
(9)
[5-(5-Chloro-2-methoxyphenyl)-3-[(2-dimethylaminoethylcarbamoyl]benzoyl]gu
anidine.dihydrochloride
mp: 195-197.degree. C.
IR (Nujol): 3250, 1700, 1640, 1240 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.84 (6H, s), 3.27-3.37 (2H, m), 3.65-3.75
(2H, m), 3.81 (3H, s), 7.21 (1H, d, J=8.8 Hz), 7.48 (1H, dd, J=8.8, 2.6
Hz), 7.63 (1H, d, J=2, 6 Hz), 8.32 (1H, s), 8.41 (1H, s), 8.61 (1H, s),
8.76 (4H, s), 9.12 (1H, t, J=5.3 Hz), 10.42 (1H, br s), 12.30 (1H, s)
(+) APCI MASS: 418 [M+H].sup.+, 420 [M+H.sup.+
(10)
[5-(2-Chloro-5-methoxyphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]g
uanidine.dihydrochloride
mp: 235-237.degree. C.
IR (Nujol): 3300, 1710, 1660, 1600, 1530, 1240 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.83 (6H, s), 3.27-3.40 (2H, m), 3.64-3.77
(2H, m), 3.86 (3H, s), 7.05 (1H, dd, J=8.8, 3.0 Hz), 7.24 (1H, d, J=3.0
Hz), 7.52 (1H, d, J=8.8 Hz), 8.33 (1H, s), 8.40 (1H, s), 8.67 (1H, s),
8.76 (4H, s), 9.16 (1H, t, J=5.3 Hz), 10.44 (1H, br s), 12.40 (1H, s)
(+) APCI MASS: 418 [M+H].sup.+, 420 [M+H].sup.+
(11)
[5-(2,5-Dimethylphenyl)-3-((2-dimethylaminoethyl)carbamoyl]benzoyl]guanidi
ne.dihydrochloride
mp: 160-163.degree. C.
IR (Nujol): 1715, 1645, 1240, 720 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.24 (3H, s), 2.32 (3H, s), 2.82 (6H, s),
3.2-3.5 (2H, m), 3.6-3.8 (2H, m), 7.1-7.3 (3H, m), 8.18 (1H, s), 8.30 (1H,
s), 8.63 (1H, s), 8.79 (4H, s), 9.12 (1H, t, J=5.2 Hz), 10.45 (1H, br s),
12.27 (1H, s)
(+) APCI MASS: 382 [M+H].sup.+
(12)
(5-(2,5-Dichlorophenyl)-3-[(2-morpholinoethyl)-carbamoyl]benzoyl]guanidine
.dihydrochloride
mp: 248-249.degree. C. (dec.)
IR (Nujol): 3300, 1690, 1645, 1100, 745 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 3.0-3.65 (6H, m), 3.65-4.1 (6H, m), 7.57 (1H,
dd, J=8.6, 2.4 Hz), 7.67 (1H, d, J=8.6 Hz), 7.77 (1H, d, J=2.4 Hz), 8.33
(1H, s), 8.39 (1H, s), 8.55-8.90 (5H, br s), 9.18 (1H, t, J=5.5 Hz), 11.02
(1H, br), 12.31 (1H, s)
(+) APCI MASS: 464 [M+H].sup.+, 466 [M+H].sup.+(13)
[5-(2,5-Dichlorophenyl)-3-[(3-dimethylaminopropyl)-carbamoyl]benzoyl]guani
dine.dihydrochloride
mp: 159.degree. C. (dec.)
IR (Nujol): 3260, 1710, 1625, 1230, 720 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.85-2.10 (2H, m), 2.75 (3H, s), 2.76 (3H, s),
3.10-3.30 (2H, m), 3.30-3.50 (2H, m), 7.57 (1H, dd, J=8.6, 2.4 Hz), 7.67
(1H, d, J=8.6 Hz), 7.75 (1H, d, J=2.4 Hz), 8.25 (1H, s), 8.35 (1H, s),
8.72 (1H, s), 8.75 (4H, s), 8.95 (1H, t, J=5.2 Hz), 10.46 (1H, br), 72.41
(1H, s)
(+) APCI MASS: 436 [M+H].sup.+, 438 [M+H].sup.+
(14)
[5-(2,5-Dimethoxyphenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]guanid
ine.dihydrochloride
mp: 187-189.degree. C.
IR (Nujol): 1710, 1685, 1220, 1010, 800, 720 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.83 (6H, s), 3.35-3.50 (2H, m), 3.6-3.8 (2H,
m), 3.73 (3H, s), 3.80 (3H, s), 6.9-7.2 (3H, m), 8.33 (1H, s), 8.40 (1H,
s), 8.58 (1H, s), 8.74 (4H, s), 9.09 (1H, t, J=5.2 Hz), 10.32 (1H, br),
12.27 (1H, s)
(+) APCI MASS: 414 [M+H].sup.+
(15)
[5-(2,5-Dichlorophenyl)-3-[(3-diethylaminopropyl)-carbamoyl]benzoyl]guanid
ine.dihydrochloride
mp: 231-233.degree. C.
IR (Nujol): 3300 (br), 1700, 1650, 1520, 1250 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 1.22 (6H, t, J=7.2 Hz), 1.90-2.08 (2H, m),
3.05-3.22 (6H, m), 3.35-3.50 (2H, m), 7.57 (1H, dd, J=8.6, 2.4 Hz), 7.68
(1H, d, J=8.6 Hz), 7.76 (1H, d, J=2.4 Hz), 8.26 (1H, s), 8.36 (1H, s),
8.72 (1H, s), 8.75 (4H, s), 8.97 (1H, t, J=5.3 Hz), 10.41 (1H, br s),
12.42 (1H, s)
(+) APCI MASS: 464 [M+H].sup.+, 466 [M+H].sup.+
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